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Management of ARDS – What Works and What Does Not

Published:December 26, 2020DOI:https://doi.org/10.1016/j.amjms.2020.12.019

      Abstract

      Acute respiratory distress syndrome (ARDS) is a clinically and biologically heterogeneous disorder associated with a variety of disease processes that lead to acute lung injury with increased non-hydrostatic extravascular lung water, reduced compliance, and severe hypoxemia. Despite significant advances, mortality associated with this syndrome remains high. Mechanical ventilation remains the most important aspect of managing patients with ARDS. An in-depth knowledge of lung protective ventilation, optimal PEEP strategies, modes of ventilation and recruitment maneuvers are essential for ventilatory management of ARDS. Although, the management of ARDS is constantly evolving as new studies are published and guidelines being updated; we present a detailed review of the literature including the most up-to-date studies and guidelines in the management of ARDS. We believe this review is particularly helpful in the current times where more than half of the acute care hospitals lack in-house intensivists and the burden of ARDS is at large.

      Key Indexing Terms

      Introduction

      Acute respiratory distress syndrome (ARDS) was first recognized as a distinct clinical entity in the 1960s. Ashbaugh presented a case series of twelve patients in respiratory failure with hypoxia and loss of compliance after a variety of clinical insults. These patients did not respond to usual methods of respiratory therapy and positive end-expiratory pressure (PEEP) was most helpful in combating atelectasis and hypoxemia. The clinical and pathological features closely resembled those seen in infants with respiratory distress and hence these patients were described as having acute respiratory distress in adults.
      • Ashbaugh D
      • Boyd Bigelow D
      • Petty T
      • Levine B
      Acute respiratory distress in adults.
      Since then we have made remarkable advances in terms of understanding the disease pathology and more importantly management of patients with ARDS. ARDS affects approximately 200,000 individuals and results in 74,500 deaths per year in the United States and globally about 3 million cases each year. Patients with ARDS represent about 10% of ICU admissions, 25% of patients require mechanical ventilation and mortality ranges from 35% to 46%.
      • Rubenfeld GD
      • Caldwell E
      • Peabody E
      • et al.
      Incidence and outcomes of acute lung injury.
      ,
      • Bellani G
      • Laffey JG
      • Pham T
      • et al.
      Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.
      Since the initial description of ARDS in 1967,
      • Ashbaugh D
      • Boyd Bigelow D
      • Petty T
      • Levine B
      Acute respiratory distress in adults.
      the definition of ARDS has undergone multiple revisions and currently the most accepted definition of ARDS known as the Berlin definition of ARDS (Table 1) is formulated by European Society of Intensive Care Medicine (ESICM) and endorsed by American Thoracic Society (ATS) and Society of Critical Care Medicine (SCCM).
      • Ranieri VM
      • Rubenfeld GD
      • Thompson BT
      • et al.
      Acute respiratory distress syndrome: the Berlin definition.
      ,
      • Bernard GR
      • Artigas A
      • Brigham KL
      • et al.
      The American-European consensus conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.
      The clinical course and prognosis depends on the severity of ARDS which is defined by the severity of hypoxemia.
      • Ranieri VM
      • Rubenfeld GD
      • Thompson BT
      • et al.
      Acute respiratory distress syndrome: the Berlin definition.
      TABLE 1Current Definition of ARDS.
      The Berlin definition of ARDS
      TimingWithin one week of a known clinical insult or new or worsening respiratory symptoms
      Chest ImagingBilateral opacities—not fully explained by effusions, lobar/lung collapse, or nodules
      Origin of pulmonary edemaRespiratory failure not fully explained by cardiac failure or fluid overload

      Need objective assessment (eg, echocardiography) to exclude hydrostatic

      edema if no risk factor is present
      MildModerateSevere
      OxygenationPaO2/FIO2 >200 mmHg but ≤300 mmHg with PEEP or CPAP 5 cm≥ H2OPaO2/FIO2 >100 mmHg but ≤200 mmHg with PEEP≥ 5 cm H2OPaO2/FIO2 ≤100 mmHg with PEEP ≥ 5 cm H2O
      Patients with certain clinical conditions are at higher risk for developing ARDS. These can broadly be grouped into direct lung injury risk factors like pneumonia, aspiration, pulmonary contusion, inhalational injury, near drowning etc. and indirect lung injury risk factors such as sepsis, non-thoracic injuries/hemorrhagic shock, pancreatitis, burns, drugs/toxins, blood transfusions, cardiopulmonary bypass and reperfusion injury after lung transplant or embolectomy.
      • Thompson BT
      • Chambers RC
      • Liu KD
      Acute respiratory distress syndrome.
      Pathophysiologically, ARDS is diffuse alveolar damage and any of the above clinical insults can activate alveolar macrophages to release pro-inflammatory cytokines such as TNF, IL-1, IL-6 and IL-8.,
      • Ware LB
      • Matthay MA
      The acute respiratory distress syndrome.
      These cytokines attract neutrophils to the lungs where they damage the alveolar and capillary epithelium by release of toxic mediators. This leads to the alveoli being filled with bloody, proteinaceous fluid and the surfactant can no longer support the alveoli.
      • Ware LB
      • Matthay MA
      The acute respiratory distress syndrome.
      • Piantadosi CA
      • Schwartz DA
      The acute respiratory distress syndrome.
      • Ware LB
      • Matthay MA
      Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome.
      The end results are that these damaged alveoli cause impaired gas exchange and decreased compliance which is the hallmark of ARDS.
      According to the most recent data, almost half (48%) of acute care hospitals lack intensivist and patients in the ICU are managed by internists/generalists.
      • Halpern NA
      • Tan KS
      • DeWitt M
      • Pastores SM
      Intensivists in U.S. acute care hospitals*.
      Since patients with ARDS represent a significant proportion of patients in the ICU, we believe that this concise up-to-date review of management of ARDS will be particularly be helpful for general physicians working in ICUs.

      Management of ARDS

      To date, there are no specific drugs or therapies available to directly treat/prevent ARDS. Mechanical ventilation with an aim to minimize Ventilator Induced Lung Injury (VILI) and management of refractory hypoxemia are the keystones in supportive management of ARDS.
      • Fan E
      • Brodie D
      • Slutsky AS
      Acute respiratory distress syndrome: advances in diagnosis and treatment.
      We will review the recommended ventilator strategies, various pharmacological and nonpharmacological therapies available and current recommendations for optimal management of patients with ARDS.

      Mechanical Ventilation

      ARDS is a heterogeneous process within the lungs in which some alveoli will never inflate, some will open and close cyclically while others will be continuously distended and damaged.
      • Gattinoni L
      • Tonetti T
      • Quintel M
      Regional physiology of ARDS.
      Therefore, the effective lung being ventilated is much smaller than usual and is termed ‘baby lung’. The primary mechanism of VILI is tidal hyperinflation of the ‘baby lung’ and cyclic atelectasis of already injured lung units.
      • Terragni PP
      • Rosboch G
      • Tealdi A
      • et al.
      Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome.
      Low tidal volume ventilation to prevent tidal hyperinflation and application of positive end expiratory pressure (PEEP) to improve hypoxemia and limit cyclic atelectasis are the key aspects of lung protective ventilation in ARDS.
      • Fan E
      Ventilatory management of acute lung injury and acute respiratory distress syndrome.
      Multiple other aspects of mechanical ventilation such as modes of ventilation,
      • Rittayamai N
      • Katsios CM
      • Beloncle F
      • Friedrich JO
      • Mancebo J
      • Brochard L
      Pressure-controlled vs volume-controlled ventilation in acute respiratory failure.
      • González M
      • Arroliga AC
      • Frutos-Vivar F
      • et al.
      Airway pressure release ventilation versus assist-control ventilation: a comparative propensity score and international cohort study.
      • Mireles-Cabodevila E
      • Kacmarek RM
      Should airway pressure release ventilation be the primary mode in ARDS?.
      • Varpula T
      • Valta P
      • Niemi R
      • Takkunen O
      • Hynynen M
      • Pettilä V
      Airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome.
      recruitment maneuvers,
      • Suzumura EA
      • Amato MBP
      • Cavalcanti AB
      Understanding recruitment maneuvers.
      ,
      • Cui Y
      • Cao R
      • Wang Y
      • Li G
      Lung recruitment maneuvers for ARDS patients: a systematic review and meta-analysis.
      higher versus lower PEEP
      • Briel M
      • Meade M
      • Mercat A
      • et al.
      Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis.
      have all been studied and described below. The current recommendations for mechanical ventilation in ARDS are represented in Table 2.
      TABLE 2Ventilatory maneuvers in the management of ARDS and their effect on outcome
      Mechanical Ventilation InterventionOutcomeGuidelines
      Lung protective ventilation (tidal volume of 4–8 mL/Kg predicted body weight and plateau pleasure of <30 cm H2O)Mortality benefit and all other measuresStrong recommendation in all ARDS patients
      Higher PEEPMortality benefit in severe ARDSConditional recommendation
      Recruitment maneuversMortality benefit in some meta analysesConditional recommendation
      Volume control versus Pressure controlNo difference in mortality or lung compliance or gas exchangeNo recommendation
      Driving pressure (Plateau pressure – PEEP)Increased mortality with increasing driving pressuresNo recommendation
      APRV/BiLevel mode of ventilationNo benefitNo recommendation
      High frequency oscillatory ventilation (HFOV)HarmStrong recommendation against the use

      Lung Protective Ventilation

      Lung protective ventilation is the cornerstone of ARDS management. The ARDSnet study published in 2000 was the most influential trial to demonstrate the clinical value of low tidal volume ventilation.
      • Brower RG
      • Matthay MA
      • Morris A
      • Schoenfeld D
      • Thompson BT
      • Wheeler A
      Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
      This randomized control trial involving 861 patients showed significantly reduced mortality (31% vs. 39.8%, p = 0.007) in patients treated with lower tidal volumes (mean tidal volumes of 6.2 ± 0.8 mL per Kg of predicted body weight) compared to patients treated with traditionally high volumes (11.8 ± 0.8 mL per Kg of predicted body weight). The mean plateau pressures were 25 ± 6 and 33 ± 8 cmH2O (p < 0.001), respectively. Subsequently, a meta-analysis of six randomized control studies comparing ventilation using tidal volume of 7 mL/Kg or less versus ventilation that used tidal volume of 10–15 mL/Kg showed that in 1297 patients with ARDS, the 28-day mortality was significantly lower in low tidal volume group compared to high tidal volume group (27.3% vs 36.9%).
      • Petrucci N
      • De Feo C.
      Lung protective ventilation strategy for the acute respiratory distress syndrome.
      Furthermore, the mortality rate in the control group was not significantly different if a plateau pressure of 31 cmH2O or less was maintained.
      When using low tidal volumes for lung protective ventilation, we are often encountered with hypercapnia resulting from low minute ventilation. Permissive hypercapnia is a concept of ‘permitting’ higher than normal level of arterial carbon dioxide so that lung protective ventilation can be continued. Previous studies have not defined a ‘safe’ permitted levels of arterial carbon dioxide or lower limit of pH for metabolic acidosis.
      • Feihl F
      • Perret C
      Permissive hypercapnia. How permissive should we be?.
      Most experts suggest continuing lung protective ventilation and treating metabolic acidosis with sodium bicarbonate when pH level is below 7.2.
      • Tobin MJ
      Culmination of an era in research on the acute respiratory distress syndrome.
      Extracorporeal removal of carbon dioxide (ECCO₂ R) is currently being studied; is another strategy to maintain low tidal volumes or reduce tidal volumes to even lower levels of approximately 3 mL/Kg of predicted body weight (sometimes referred to as ultra-protective ventilation). Although there are no studies comparing administration of sodium bicarbonate versus extracorporeal CO2 removal, ECCO₂ R has a potential to further reduce VILI compared with the lung protective ventilation.
      • Bein T
      • Weber-Carstens S
      • Goldmann A
      • et al.
      Lower tidal volume strategy (≈3 ml/kg) combined with extracorporeal CO2 removal versus ‘conventional’ protective ventilation (6 ml/kg) in severe ARDS: The prospective randomized Xtravent-study.
      • Morales-Quinteros L
      • Camprubí-Rimblas M
      • Bringué J
      • Bos LD
      • Schultz MJ
      • Artigas A
      The role of hypercapnia in acute respiratory failure.
      • Goligher EC
      • Combes A
      • et al.
      (ECMONet) for the S investigators (European S of ICM trials group) and for the IEN
      Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial: implications for trial design.
      Whether this strategy will improve survival in ARDS patients remains to be determined.
      In conclusion, it is strongly recommended to use lung protective ventilation (tidal volume of 4–8 mL/Kg of predicted body weight and to maintain plateau pleasure of < 30 cmH2O) in all ARDS patients.

      Positive End Expiratory Pressure

      As mentioned above, low tidal volume ventilation to prevent tidal hyperinflation and application of positive end expiratory pressure (PEEP) to prevent atelectrauma are the main components of lung protective ventilation in patients with ARDS. PEEP helps in alveolar recruitment, prevents subsequent re-collapse of these difficult to recruit lung units and thereby improving oxygenation and reducing lung stress and strain. Potential risks from using PEEP include injury from alveolar overdistension, increased intrapulmonary shunting, increased dead space and higher pulmonary vascular resistance.
      • Fan E
      Ventilatory management of acute lung injury and acute respiratory distress syndrome.
      ,
      • Plötz FB
      • Slutsky AS
      • van Vught AJ
      • Heijnen CJ
      Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses.
      While there is no strict definition of what constitutes a higher PEEP versus lower PEEP, most of the published studies have used a lower PEEP/higher FiO2 or higher PEEP/lower FiO2 values that were used by the ARDSnet group in their landmark trial.
      • Briel M
      • Meade M
      • Mercat A
      • et al.
      Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis.
      ,
      • Brower RG
      • Lanken PN
      • MacIntyre N
      • et al.
      Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.
      The trial suggests that their PEEP/FIO2 titration tables represent the best method for adjusting these variables (Tables 3.1 and 3.2). A meta-analysis involving 2299 patients who received higher PEEP vs lower PEEP (mean PEEP in high PEEP vs. low PEEP groups were 15.3 vs 9 on day 1, 13.3 vs. 8.2 on day 3 and 10.8 vs. 7.8 on day 7 respectively) showed that in patients with ARDS, treatment with higher PEEP was associated with relative mortality reduction of 10% with no serious adverse effects compared to lower PEEP.
      • Briel M
      • Meade M
      • Mercat A
      • et al.
      Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis.
      TABLE 3.1Lower PEEP/higher FiO2.
      FiO20.30.40.40.50.50.60.70.70.70.80.90.90.91.0
      PEEP558810101012141414161818–24
      TABLE 3.2Higher PEEP/lower FiO2.
      FiO20.30.30.30.30.30.40.40.50.50.5–0.80.80.91.01.0
      PEEP58101214141616182022222224
      In summary, while PEEP is recommended in all patients with ARDS, high PEEP may be considered on a case-by-case basis (conditional recommendation) in patients with moderate to severe ARDS.

      Recruitment Maneuvers

      A recruitment maneuver is a ventilator intervention to transiently increase airway pressure to open the collapsed alveoli, thereby improving oxygenation and volume distribution.
      • Fan E
      • Wilcox ME
      • Brower RG
      • et al.
      Recruitment maneuvers for acute lung injury: a systematic review.
      Although the recruitment process can be accomplished by various methods, the most commonly used methods in various studies are sustained inflation/traditional and incremental PEEP/staircase/stepwise recruitment maneuver.
      • Goligher EC
      • Combes A
      • et al.
      (ECMONet) for the S investigators (European S of ICM trials group) and for the IEN
      Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial: implications for trial design.
      ,
      • Narendra DK
      • Hess DR
      • Sessler CN
      • et al.
      Update in management of severe hypoxemic respiratory failure.
      Sustained inflation involves changing the ventilator to CPAP mode and using pressures of 35–50 cmH2O for 20–40 s while ensuring that the pressure support is set to zero to avoid additional pressure increases.
      • Lapinsky SE
      • Mehta S
      Bench-to-bedside review: Recruitment and recruiting maneuvers.
      A staircase or incremental PEEP strategy uses stepwise increase in PEEP every 2–3 min while maintaining constant driving pressure (plateau pressure – PEEP), followed by stepwise decrease in PEEP to the optimal PEEP level which is determined by compliance and oxygenation.
      • Suzumura EA
      • Amato MBP
      • Cavalcanti AB
      Understanding recruitment maneuvers.
      ,
      • Lapinsky SE
      • Mehta S
      Bench-to-bedside review: Recruitment and recruiting maneuvers.
      Since the recruitment maneuvers involve using high pressures, it is prudent to monitor the patient closely for hypoxia and hemodynamic instability. A meta-analysis involving 10 trials and 1658 patients showed that in patients with ARDS where recruitment maneuvers were employed, there was reduction in ICU mortality but no difference in 28-day hospital mortality.
      • Hodgson C
      • Goligher EC
      • Young ME
      • et al.
      Recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation.
      A more recent meta-analysis with 2755 patients showed no reduction in 28-day mortality, ICU mortality or in-hospital mortality.
      • Kang H
      • Yang H
      • Tong Z
      Recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation: a systematic review and meta-analysis.
      Subgroup analyses of these RCTs showed that traditional recruitment maneuver was associated with significantly reduced mortality while stepwise maneuver was associated increased moratlity.
      • Alhazzani W
      • Møller MH
      • Arabi YM
      • et al.
      Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19).
      However, an influential RCT published in 2017 that included 1010 patients greatly informs the current view on recruitment maneuvers. It concluded that in patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP resulted in increased 28-day all-cause mortality. These results did not support the routine use of lung recruitment maneuver and PEEP titration in these patients.
      • Cavalcanti AB
      • Suzumura ÉA
      • Laranjeira LN
      • et al.
      Effect of lung recruitment and titrated Positive End-Expiratory Pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome – a randomized clinical trial.
      A significant number of these studies are at risk of bias because of concomitant co-interventions in the recruitment maneuver group. However, most of these studies have shown that recruitment maneuvers help in improving oxygenation without increasing risk of barotrauma or other serious adverse events.
      • Suzumura EA
      • Amato MBP
      • Cavalcanti AB
      Understanding recruitment maneuvers.
      ,
      • Fan E
      • Wilcox ME
      • Brower RG
      • et al.
      Recruitment maneuvers for acute lung injury: a systematic review.
      ,
      • Kang H
      • Yang H
      • Tong Z
      Recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation: a systematic review and meta-analysis.
      Thus the evidence for the use of recruitment maneuvers is mixed and does not support the routine use of recruitment maneuvers in management of patients with ARDS. This modality may be considered in selective patients with severe ARDS and persistent hypoxemia.

      Modes of Ventilation

      The traditional ventilator modes that are commonly used for patients with ARDS include pressure-controlled ventilation (PCV) or volume-controlled ventilation (VCV). Inverse ratio ventilation (IRV) is a strategy which can be applied to either of these modes that essentially reverses the inspiratory to expiratory (I:E) ratio. A typical I:E ratio for most patients is 1:2 or more and thereby mimics normal physiologic breathing where the expiratory phase of a breath is longer than the inspiratory phase. IRV is most often used in conjunction with pressure-controlled ventilation (PC-IRV) where the I:E ratio can be inverted to 2:1, 3:1 or more to spend significantly more time in the inspiratory phase which in turn increases the mean airway pressure, oxygenation and gas exchange.

      Sembroski E, Sanghavi D, Bhardwaj A. Inverse ratio ventilation.; 2020. http://www.ncbi.nlm.nih.gov/pubmed/30571016. Accessed July 12, 2020.

      A systematic review and meta-analysis of 34 studies showed no difference in mortality, compliance or oxygenation when comparing PCV, VCV and PC-IRV.
      • Rittayamai N
      • Katsios CM
      • Beloncle F
      • Friedrich JO
      • Mancebo J
      • Brochard L
      Pressure-controlled vs volume-controlled ventilation in acute respiratory failure.
      Nontraditional modes of ventilation that are sometimes used in the setting of ARDS include airway pressure release ventilation (APRV) and high frequency oscillatory ventilation (HFOV).
      • Narendra DK
      • Hess DR
      • Sessler CN
      • et al.
      Update in management of severe hypoxemic respiratory failure.
      APRV was initially described in 1987 but did not gain popularity until the last 2 decades due to continued efforts to describe best ventilator strategies for patients with ARDS. APRV uses a continuous positive airway pressure (CPAP) with an intermittent release phase. This can be achieved by applying CPAP (P high) for a prolonged time (T high) to maintain adequate lung volume and alveolar recruitment with a time cycled release phase to lower set pressure (P low) for a short period of time (T low) during which most of the carbon dioxide is removed. APRV also allows the patient to breathe spontaneously throughout both these cycles with added pressure support (PS).
      • Narendra DK
      • Hess DR
      • Sessler CN
      • et al.
      Update in management of severe hypoxemic respiratory failure.
      ,
      • Daoud E
      Airway pressure release ventilation.
      It is to be noted that in the absence of spontaneous breathing, APRV would essentially be similar to pressure-controlled inverse ratio ventilation (PC-IRV). To date no large studies have demonstrated that APRV is superior to conventional modes of ventilation in patients with ARDS, however a randomized controlled trial comparing APRV to conventional low tidal volume ventilation reported no difference in mortality but led towards increased ventilator days, ICU days and ventilator associated pneumonia in the APRV group.
      • Maxwell RA
      • Green JM
      • Waldrop J
      • et al.
      A randomized prospective trial of airway pressure release ventilation and low tidal volume ventilation in adult trauma patients with acute respiratory failure.
      Similarly, an observational study in 349 ICUs in 23 countries did not demonstrate any improvements in outcomes with APRV.
      • González M
      • Arroliga AC
      • Frutos-Vivar F
      • et al.
      Airway pressure release ventilation versus assist-control ventilation: a comparative propensity score and international cohort study.
      High frequency oscillatory ventilation (HFOV) is another non-traditional mode of ventilation where very low tidal volumes (1-2mL/Kg) are delivered at high frequencies (3-15 Hz). HFOV is hardly used due to evidence that showed no mortality benefit and one study showing increased mortality in moderate ARDS in the HFOV group compared to conventional ventilation.
      • Fan E
      • Brodie D
      • Slutsky AS
      Acute respiratory distress syndrome: advances in diagnosis and treatment.
      ,
      • Narendra DK
      • Hess DR
      • Sessler CN
      • et al.
      Update in management of severe hypoxemic respiratory failure.
      A more recent meta-analysis by Meade et al
      • Meade MO
      • Young D
      • Hanna S
      • et al.
      Severity of hypoxemia and effect of high-frequency oscillatory ventilation in acute respiratory distress syndrome.
      suggests that HFOV increases mortality in most patients with ARDS but may benefit patients with severe hypoxemia on conventional mechanical ventilation. Driving pressure (plateau pressure – PEEP) is another ventilator variable that has been studied in recent years. A retrospective analysis of 9 clinical trials showed that among ventilator variables such as tidal volume, plateau pressure and driving pressure, the driving pressure best predicted survival in patients with ARDS even when receiving lung protective ventilation.
      • Amato MBP
      • Meade MO
      • Slutsky AS
      • et al.
      Driving pressure and survival in the acute respiratory distress syndrome.
      A large observational study showed that driving pressures greater than 14 cmH2O was associated with increased mortality and strategies that led to lower driving pressures (<15 cm of H2O) was strongly associated with improved survival.
      • Bellani G
      • Laffey JG
      • Pham T
      • et al.
      Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.
      ,
      • Amato MBP
      • Meade MO
      • Slutsky AS
      • et al.
      Driving pressure and survival in the acute respiratory distress syndrome.
      ,
      • Wei X
      • Wang Z
      • Liao X
      • Guo W
      • Qin T
      • Wang S
      Role of neuromuscular blocking agents in acute respiratory distress syndrome: an updated meta-analysis of randomized controlled trials.
      In summary, standard modes of ventilation (VC or PC) are recommended in patients with ARDS. There is no evidence that alternative modes of ventilation such as pressure controlled inverse ratio or airway pressure release ventilation provide additional benefit. On the other hand, HFOV is not recommended in the management of patients with moderate to severe ARDS.

      Pharmacological Interventions

      Over the last two decades multiple pharmacological agents have been studied in the management of ARDS. The proposed mechanism of these agents includes either decreasing the inflammatory cascade, fastening the recovery of injured alveoli or reducing ventilator dyssynchrony, thus reducing VILI.
      • Fan E
      • Brodie D
      • Slutsky AS
      Acute respiratory distress syndrome: advances in diagnosis and treatment.
      Neuromuscular blockers and systemic corticosteroids are the most extensively studied agents in this aspect.

      Neuromuscular Blockers (NMB)

      The proposed mechanism of action of how neuromuscular blocking agents can be helpful in patients with ARDS is unclear and hypothetical. Patients with ARDS have high inflammatory burden, higher metabolic rate and hypercarbia due to low tidal volume ventilation. All of these factors can increase the ventilatory drive resulting in higher risk of patient-ventilator dyssynchrony and subsequently barotrauma and volutrauma.
      • Wei X
      • Wang Z
      • Liao X
      • Guo W
      • Qin T
      • Wang S
      Role of neuromuscular blocking agents in acute respiratory distress syndrome: an updated meta-analysis of randomized controlled trials.
      NMBs can achieve better patient-ventilator synchrony by relaxing the smooth muscles and when administered early in the course of ARDS, NMBs are also thought to decrease pro-inflammatory responses.
      • Wei X
      • Wang Z
      • Liao X
      • Guo W
      • Qin T
      • Wang S
      Role of neuromuscular blocking agents in acute respiratory distress syndrome: an updated meta-analysis of randomized controlled trials.
      The first randomized controlled trial (ACURASYS) that established the beneficial role was a French study published in 2010.
      • Papazian L
      • Forel J-M
      • Gacouin A
      • et al.
      Neuromuscular blockers in early acute respiratory distress syndrome.
      This study randomized 340 patients with an onset of severe ARDS (P/F ratio < 150) within the previous 48 hours to receive cisatracurium or placebo for 48 h. The results showed reduction in 90-day mortality in the cisatracurium group (30.8%) compared to the control group (44.6%). The cisatracurium group also had less time on ventilator and both groups had similar rates of ICU-acquired weakness. A meta-analyses of 3 randomized control trials with 431 patients also showed similar findings with short term infusion of cisatracurium in patients with severe ARDS.
      • Alhazzani W
      • Alshahrani M
      • Jaeschke R
      • et al.
      Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials.
      ,
      • Neto AS
      • Pereira VGM
      • Espósito DC
      • Damasceno MCT
      • Schultz MJ.
      Neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials.
      However, the most recently published randomized control trial (ROSE) in the United States with 1006 patients with moderate to severe ARDS showed that there was no difference in 90-day mortality between patients who received an early and continuous cisatracurium infusion and those who were treated with a lighter sedation approach.
      • Moss M
      • Huang DT
      • Brower RG
      • et al.
      Early neuromuscular blockade in the acute respiratory distress syndrome.
      It is hypothesized that the ROSE trial failed to show the benefit of NMBs because the patients in this trial received higher average PEEP compared to ACURASYS trial, less patients received prone positioning in the ROSE trial compared to ACURASYS and only the intervention group in ROSE was deeply sedated versus all the patients in ACURASYS. This all added bias and confounding factors to the study. Given the current conflicting evidence it is reasonable to conclude that NMBs should not be routinely used in all severe ARDS patients and are likely beneficial only in selective patients with severe ARDS with refractory hypoxemia, patient-ventilator dyssynchrony and high risk of barotrauma. This is especially true as more recent meta-analysis and a randomized controlled study showed increased ICU-acquired weakness and possibly cardiovascular adverse events with use of NMBs.
      • Wei X
      • Wang Z
      • Liao X
      • Guo W
      • Qin T
      • Wang S
      Role of neuromuscular blocking agents in acute respiratory distress syndrome: an updated meta-analysis of randomized controlled trials.
      ,
      • Moss M
      • Huang DT
      • Brower RG
      • et al.
      Early neuromuscular blockade in the acute respiratory distress syndrome.
      In summary, the use of NMBs in patients with moderate to severe ARDS should be individualized for patients based on practitioner's experience, facility protocols, and equipment/staff availability.

      Systemic Corticosteroids

      Due to their potent anti-inflammatory activity, systemic corticosteroids have been of huge interest in the treatment of patients with ARDS. Different agents and regimens have been studied previously but overall results have been inconclusive in terms of mortality benefit. Contrary, new studies provide conclusive evidence on the safety and efficacy of this treatment intervention.
      • Steinberg KP
      • Hudson LD
      • Goodman RB
      • et al.
      Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.
      • Meduri GU
      • Golden E
      • Freire AX
      • et al.
      Methylprednisolone infusion in early severe ARDS.
      • Tongyoo S
      • Permpikul C
      • Mongkolpun W
      • et al.
      Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial.
      • Villar J
      • Ferrando C
      • Martínez D
      • et al.
      Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.
      Most of the RCTs are confounded by the fact that the studies either did not consistently use lung protective ventilation or did not report such data. The ARDSnet study which incorporated the lung protective ventilation randomized 180 patients with ARDS of at least 7 days duration to receive either methylprednisolone or placebo and found no difference in 60-day mortality. In addition, 60-day and 180-day mortality was higher if methylprednisolone was started after 2 weeks of onset of ARDS.
      • Steinberg KP
      • Hudson LD
      • Goodman RB
      • et al.
      Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.
      However, in follow up publications, the ARDS network provided the following correction: after adjustment for large baseline imbalances there was no difference in mortality in patients randomized after day 14. Another similar study randomized 197 patients with ARDS due to severe sepsis within 12 hours of ARDS onset to receive hydrocortisone or placebo showed no survival benefit at 28 days.
      • Tongyoo S
      • Permpikul C
      • Mongkolpun W
      • et al.
      Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial.
      Both studies did show improved cardiopulmonary parameters such as number of ventilator free days, shock free days, fewer days on vasopressors, improvement in respiratory system compliance and ICU free days in the intervention arm during the first 28 days of treatment with steroids. Most recently, a randomized control study that used dexamethasone in patients with ARDS showed that dexamethasone administered within 30 hours of onset of moderate to severe ARDS led to improved 60-day mortality (21% vs, 36%, p=0.0047) and increased ventilatory free days at 28 days of randomization when compared to placebo. The major adverse events were similar in both groups and the most common adverse event in the corticosteroid group was hyperglycemia in ICU. This new landmark study provides conclusive evidence on the safety and efficacy of corticosteroids.
      • Villar J
      • Ferrando C
      • Martínez D
      • et al.
      Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.
      A 2016 meta-analysis included an individual patient data (IPD) meta-analysis (IPDMA) of four small-to-moderate size RCTs (n=322) investigating methylprednisolone in early and late ARDS. Compared with late (≥ 7 days) intervention, early (< 72 h) initiation of methylprednisolone treatment, when fibroproliferation is still in the early stage of development, is associated with faster disease resolution as measured by time to extubation (HR=3.48; 95% CI 2.07–5.85; p < 0.001 vs. HR=2.06; 95% CI 1.44–2.95; p < 0.0001) and ICU discharge, despite a lower daily methylprednisolone dose (1mg/Kg/day versus 2mg/Kg/day). The IPDMA also provided evidence that premature discontinuation of treatment is associated with reconstituted systemic inflammation with return to mechanical ventilation and worse outcomes if corticosteroids are not reinstituted.
      • Meduri GU
      • Bridges L
      • Shih MC
      • Marik PE
      • Siemieniuk RAC
      • Kocak M
      Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature.
      Based on the evidence provided in an updated report of aggregate data from 10 randomized studies (n = 1093) that was recently provided in a commentary by Villar el al.,
      • Villar J
      • Confalonieri M
      • Pastores SM
      • Meduri GU
      Rationale for prolonged corticosteroid treatment in the acute respiratory distress syndrome caused by Coronavirus Disease 2019.
      the Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) suggested that corticosteroid use is associated with a sizable reduction in duration of mechanical ventilation (MV) and hospital mortality. Mean standard deviation reduction of duration of mechanical ventilation in methylprednisolone treatment vs. control [-10.10 (-13.12–7.08), p < 0.001] and dexamethasone versus control [–5.3(–8.4to–2.2), p = 0.0009].
      • Villar J
      • Confalonieri M
      • Pastores SM
      • Meduri GU
      Rationale for prolonged corticosteroid treatment in the acute respiratory distress syndrome caused by Coronavirus Disease 2019.
      There was a significant reduction in relative risk for hospital mortality (RR 0.67 95%; CI 0.52–0.87) with one life saved for seven treated patients. Lower mortality was observed with methylprednisolone treatment (RR 0.51 95%; CI 0.31–0.83).
      • Villar J
      • Confalonieri M
      • Pastores SM
      • Meduri GU
      Rationale for prolonged corticosteroid treatment in the acute respiratory distress syndrome caused by Coronavirus Disease 2019.
      For patients with moderate to severe ARDS (P/F <200), methylprednisolone should be considered at dose of 1mg/Kg/day for early (up to 7 days since onset) and at a dose of 2mg/Kg/day for late (after 7 days since onset). Methylprednisolone should be weaned slowly over 6–14 days and not stopped rapidly.
      • Annane D
      • Pastores SM
      • Rochwerg B
      • et al.
      Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in critically Ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.
      Due to blunting of febrile response when corticosteroids are used, it would be prudent to recognize and treat hospital acquired infections promptly. Methylprednisolone is suggested as the agent of choice due its greater penetration into lung tissue and longer bioavailability compared to prednisolone, however there are no RCTs comparing different corticosteroid agents in patients with ARDS.
      In conclusion, early administration of corticosteroids within 14 days of onset of moderate to severe ARDS can reduce the duration of mechanical ventilation and overall mortality and should be considered in such patients provided no contraindications.

      Inhaled Vasodilators

      Inhaled vasodilators such as inhaled nitric oxide (iNO) and inhaled prostacyclins hypothetically dilate the pulmonary blood vessels of adequately ventilated lung units thereby redirecting the blood flow from poorly ventilated lung units and improving the V/Q mismatch. However, studies in patients with ARDS have not shown any survival benefits with use of inhaled vasodilators.
      • Cherian S V
      • Kumar A
      • Akasapu K
      • Ashton RW
      • Aparnath M
      • Malhotra A
      Salvage therapies for refractory hypoxemia in ARDS.
      At this time inhaled vasodilators are not recommended for routine use but may be used as bridge while waiting for other therapies such as ECMO.
      • Narendra DK
      • Hess DR
      • Sessler CN
      • et al.
      Update in management of severe hypoxemic respiratory failure.
      Inhaled prostacyclins may be preferred over iNO in patients with refractory hypoxemia and pre-existing pulmonary hypertension. It may also be preferred by some clinicians due to its ease of delivery unlike iNO which requires a specialized delivery system.
      • Cherian S V
      • Kumar A
      • Akasapu K
      • Ashton RW
      • Aparnath M
      • Malhotra A
      Salvage therapies for refractory hypoxemia in ARDS.

      Miscellaneous

      Many other pharmacological interventions such as aspirin, intravenous salbutamol, keratinocyte growth factor, statins, granulocyte-macrophage colony stimulating factor, macrolide antibiotics, surfactant, activated protein C, ketoconazole and most recently intravenous interferon b-1a have been studied and found to have no proven benefit in patient with ARDS.
      • Kor DJ
      • Erlich J
      • Gong MN
      • et al.
      Association of prehospitalization aspirin therapy and acute lung injury: Results of a multicenter international observational study of at-risk patients*.
      • Smith FG
      • Perkins GD
      • Gates S
      • et al.
      Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial.
      • McAuley DF
      • Cross LJM
      • Hamid U
      • et al.
      Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial.
      • Xiong B
      • Wang C
      • Tan J
      • et al.
      Statins for the prevention and treatment of acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis: Statins and ALI/ARDS.
      • Paine R
      • Standiford TJ
      • Dechert RE
      • et al.
      A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury*.
      • Walkey AJ
      • Wiener RS
      Macrolide antibiotics and survival in patients with acute lung injury.
      • Willson DF
      • Truwit JD
      • Conaway MR
      • Traul CS
      • Egan EE
      The adult calfactant in acute respiratory distress syndrome trial.
      • Liu KD
      • Levitt J
      • Zhuo H
      • et al.
      Randomized clinical trial of activated protein C for the treatment of acute lung injury.
      Network TANA for the A
      Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.
      • Ranieri VM
      • Pettilä V
      • Karvonen MK
      • et al.
      Effect of intravenous interferon β-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome: a randomized clinical trial.
      Table 4 represents a detailed list of all the pharmacological agents and their outcomes in the management of ARDS.
      TABLE 4Summary of pharmacologic agents tried in the management of ARDS and outcomes.
      Pharmacological AgentOutcomeRecommendations
      Cisatracurium
      • Meduri GU
      • Golden E
      • Freire AX
      • et al.
      Methylprednisolone infusion in early severe ARDS.
      Mortality benefitWeak recommendation

      P/F <150
      Methylprednisolone
      • Kor DJ
      • Erlich J
      • Gong MN
      • et al.
      Association of prehospitalization aspirin therapy and acute lung injury: Results of a multicenter international observational study of at-risk patients*.
      Mortality benefitConditional recommendation

      P/F <200 and < 14 days
      Inhaled Nitric oxide
      • Lai-Fook SJ
      • Rodarte JR
      Pleural pressure distribution and its relationship to lung volume and interstitial pressure.
      No benefitNone
      Inhaled Prostacyclin
      • Cornejo RA
      • Díaz JC
      • Tobar EA
      • et al.
      Effects of prone positioning on lung protection in patients with acute respiratory distress syndrome.
      No benefitNone
      Aspirin
      • McAuley DF
      • Cross LJM
      • Hamid U
      • et al.
      Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial.
      No benefitNone
      Intravenous salbutamol
      • Xiong B
      • Wang C
      • Tan J
      • et al.
      Statins for the prevention and treatment of acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis: Statins and ALI/ARDS.
      HarmNone
      Keratinocyte growth factor
      • Paine R
      • Standiford TJ
      • Dechert RE
      • et al.
      A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury*.
      HarmNone
      Statins
      • Walkey AJ
      • Wiener RS
      Macrolide antibiotics and survival in patients with acute lung injury.
      No benefitNone
      Granulocyte-macrophage colony stimulating factor
      • Willson DF
      • Truwit JD
      • Conaway MR
      • Traul CS
      • Egan EE
      The adult calfactant in acute respiratory distress syndrome trial.
      InconclusiveNone
      Macrolide antibiotics
      • Liu KD
      • Levitt J
      • Zhuo H
      • et al.
      Randomized clinical trial of activated protein C for the treatment of acute lung injury.
      InconclusiveNone
      Surfactant
      Network TANA for the A
      Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.
      No benefitNone
      Activated Protein C
      • Ranieri VM
      • Pettilä V
      • Karvonen MK
      • et al.
      Effect of intravenous interferon β-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome: a randomized clinical trial.
      No benefitNone
      Ketoconazole
      • Piehl MA
      • Brown RS
      Use of extreme position changes in acute respiratory failure.
      No benefitNone
      Intravenous interferon b-1a
      • Scholten EL
      • Beitler JR
      • Prisk GK
      • Malhotra A
      Treatment of ARDS with prone positioning.
      No benefitNone

      Non-Pharmacological Interventions

      Prone Positioning

      Prone positioning was first described in 1970s as a measure to improve gas exchange in patients with ARDS.
      • Piehl MA
      • Brown RS
      Use of extreme position changes in acute respiratory failure.
      However, considerable evidence supporting the use of prone positioning for severe ARDS was published only in the last decade and more so since the COVID-19 pandemic.
      • Scholten EL
      • Beitler JR
      • Prisk GK
      • Malhotra A
      Treatment of ARDS with prone positioning.
      The mechanism by which prone positioning improves oxygenation is multifactorial. It reduces the ventral to dorsal transpulmonary pressure difference, ventilation-perfusion mismatch and lung compression.
      • Lai-Fook SJ
      • Rodarte JR
      Pleural pressure distribution and its relationship to lung volume and interstitial pressure.
      • Cornejo RA
      • Díaz JC
      • Tobar EA
      • et al.
      Effects of prone positioning on lung protection in patients with acute respiratory distress syndrome.
      • Puybasset L
      • Cluzel P
      • Chao N
      • et al.
      A computed tomography scan assessment of regional lung volume in acute lung injury.
      • Nyrén S
      • Mure M
      • Jacobsson H
      • Larsson SA
      • Lindahl SGE
      Pulmonary perfusion is more uniform in the prone than in the supine position: scintigraphy in healthy humans.
      • Jozwiak M
      • Teboul J-L
      • Anguel N
      • et al.
      Beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome.
      • Albert RK
      • Hubmayr RD
      The prone position eliminates compression of the lungs by the heart.
      In supine position, the weight of the heart and posterior abdominal viscera compress the dorsal lungs thereby increasing the dorsal pleural pressure. Furthermore, since the dorsal lung is the dependent portion, the edematous fluid filled alveoli in ARDS preferentially affects the dorsal lung alveoli further increasing the dorsal pleural pressure. Due to this pressure difference between the ventral and dorsal pleura, it would require much higher pressures to ventilate the dorsal alveoli compared to ventral alveoli. In other-words, at a given pressure or tidal volume the ventral alveoli are over-distended and the dorsal alveoli are under-distended. The over-distension of alveoli as mentioned above causes VILI resulting in increased mortality and morbidity in ARDS patients. It is also hypothesized that independent of gravitational forces, pulmonary blood flow is always directed dorsally due to architecture of the lungs, heart and blood vessels. This means that even though the dorsal alveoli are mostly collapsed, they still continue to receive more perfusion than the ventral alveoli which results in ventilation-perfusion mismatch or shunting.
      • Scholten EL
      • Beitler JR
      • Prisk GK
      • Malhotra A
      Treatment of ARDS with prone positioning.
      Prone positioning reduces the difference between the dorsal and ventral pleural pressures by decreasing compression by the heart and abdominal viscera thus making ventilation more uniform, leading to decrease in over-distension of the ventral alveoli and the previously collapsed dorsal alveoli are now recruited to participate in ventilation. The dorsal alveoli will also continue to receive more blood supply since the pulmonary blood flow is directed dorsally thereby reducing the ventilation-perfusion mismatch or shunt fraction.
      • Scholten EL
      • Beitler JR
      • Prisk GK
      • Malhotra A
      Treatment of ARDS with prone positioning.
      ,
      • Lai-Fook SJ
      • Rodarte JR
      Pleural pressure distribution and its relationship to lung volume and interstitial pressure.
      Other potential physiological effects of prone positioning include a decrease in proinflammatory cytokines and improvement in RV dysfunction by preserving pulmonary circulation.
      • Narendra DK
      • Hess DR
      • Sessler CN
      • et al.
      Update in management of severe hypoxemic respiratory failure.
      ,
      • Guerin C
      Prone ventilation in acute respiratory distress syndrome.
      Prone positioning was initially described in case series followed by a few small studies. It revealed effectiveness as a rescue measure for severe hypoxemia in ARDS and improved the P/F ratio by an average of 35 mm Hg.
      • Scholten EL
      • Beitler JR
      • Prisk GK
      • Malhotra A
      Treatment of ARDS with prone positioning.
      The first prospective randomized control trial (PROSEVA) showed mortality benefit of prolonged prone positioning was conducted in France and published in 2013.
      • Guérin C
      • Reignier J
      • Richard J-C
      • et al.
      Prone positioning in severe acute respiratory distress syndrome.
      In this multicenter study, 466 patients with severe ARDS (P/F <150 with FiO2 > 60 and PEEP > 5) were randomized within 36 hours of onset of ARDS to prone positioning for at least 16 hours/day or to be left in supine position. The results showed that the 28-day mortality (16.0% vs. 32.8%, P < 0.001) and 90-day mortality (23.6% vs. 41.0%, P<0.001) were significantly lower in the prone group. Earlier randomized control trials failed to show significant mortality benefit due inconsistent use of lung protective ventilation, shorter duration of prone positioning and application of prone positioning in patients with mild-moderate ARDS.
      • Scholten EL
      • Beitler JR
      • Prisk GK
      • Malhotra A
      Treatment of ARDS with prone positioning.
      ,
      • Sud S
      • Friedrich JO
      • Adhikari NKJ
      • et al.
      Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis.
      Several recent meta-analysis’ demonstrated significant reduction in mortality when prone positioning was used in patients with severe ARDS with concomitant lung protective ventilation and high PEEP strategy.
      • Sud S
      • Friedrich JO
      • Adhikari NKJ
      • et al.
      Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis.
      ,
      • Beitler JR
      • Shaefi S
      • Montesi SB
      • et al.
      Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis.
      Despite the evidence supporting its use, a population based observational study from ICUs in 50 countries (LUNG SAFE) showed that prone positioning was significantly underutilized (16.3%) in patients with severe ARDS.
      • Bellani G
      • Laffey JG
      • Pham T
      • et al.
      Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.
      Most of the studies conducted for prone positioning originated from European countries where the medical staff was specially trained for performing the procedure. Placing a patient in a prone position is a multistep process which requires 3-5 personnel while paying close attention to the endotracheal tube, central lines and other invasive devices in place. Most of the institutions with high volume of ICU patients now have a protocol describing the steps in detail and performing a checklist before placing a patient in a prone position. A demonstration video and a sample checklist for prone positioning are available online which can used to perform the procedure.
      • Guérin C
      • Reignier J
      • Richard J-C
      • et al.
      Prone positioning in severe acute respiratory distress syndrome.
      ,
      • Messerole E
      • Peine P
      • Wittkopp S
      • Marini JJ
      • Albert RK
      The Pragmatics of prone positioning.
      Prone positioning is contraindicated in patients with facial/neck trauma or spinal instability, recent sternotomy, large ventral surface burn, elevated intracranial pressure, massive hemoptysis and patients at high risk of requiring cardiopulmonary resuscitation (CPR) or defibrillation.
      • Narendra DK
      • Hess DR
      • Sessler CN
      • et al.
      Update in management of severe hypoxemic respiratory failure.
      ,
      • Scholten EL
      • Beitler JR
      • Prisk GK
      • Malhotra A
      Treatment of ARDS with prone positioning.
      While prone positioning has proven to be effective, manageable and well tolerated, it is prudent to be aware of the potential complications which include endotracheal tube dislodgement or kinking, vascular catheter kinking, elevated intra-abdominal pressure, transient increase in oral/tracheal secretions occluding the airway, increased gastric residuals, facial edema, pressure ulcers, lip trauma and brachial plexus injury from arm extension.
      • Scholten EL
      • Beitler JR
      • Prisk GK
      • Malhotra A
      Treatment of ARDS with prone positioning.
      Other important aspects to consider for successful implementation include early prone positioning (ideally within 48 hours) when severe hypoxemia persists after initial stabilization, prone positioning for more than 12 hours/day, strict adherence to lung protective ventilation, judicious use of neuromuscular blocking agents and procedure must be executed by trained medical staff to minimize complications. Although optimal strategy is unclear, prone positioning can be discontinued when P/F remains >150 mmHg for 4 hours after supinating (with a PEEP <10 cm H2O and FiO2 <0.6).
      • Narendra DK
      • Hess DR
      • Sessler CN
      • et al.
      Update in management of severe hypoxemic respiratory failure.
      ,
      • Scholten EL
      • Beitler JR
      • Prisk GK
      • Malhotra A
      Treatment of ARDS with prone positioning.
      Prior to the COVID-19 pandemic, there was very limited published data on prone positioning in nonintubated patients. In a pilot study, 50 non-intubated hypoxemic patients with suspected COVID-19 who presented to the emergency department in New York were found a significant increase in SpO2 5 min after proning (pre-proning: 84%, post-proning: 94%; p = 0.001).
      • Caputo ND
      • Strayer RJ
      • Levitan R
      Early self-proning in awake, non-intubated patients in the emergency department: a single ED's experience during the COVID-19 pandemic.
      There is continuous emerging data on the early application prone positioning in the awake non-intubated ARDS patient however it should still be interpreted with caution due to lack of randomized studies available. Further studies are needed however to determine the effect of proning on disease severity and mortality.
      In summary, prone positioning for more than 12 h/day is strongly recommended in ventilated patients with severe ARDS. Furthermore, well designed studies are needed on the role of early, awake self-proning in the management ARDS.

      Extracorporeal Membrane Oxygenation (ECMO)

      ECMO is an extracorporeal life support modality used to temporarily support patients with respiratory and/or cardiac failure that are refractory to conventional treatment. The venovenous ECMO (VV-ECMO) configuration is the choice in patients with respiratory failure with preserved cardiac function and the venoarterial ECMO (VA-ECMO) configuration is the choice in patients with cardiac failure with or without respiratory failure.
      • Chaves RC de F
      • Rabello Filho R
      • Timenetsky KT
      • et al.
      Extracorporeal membrane oxygenation: a literature review.
      Even though ECMO was first used in adults in the 1970s, it started gaining popularity during the 2009 H1N1 pandemic when significant improvement in survival was noted in patients with ARDS and after two large RCTs reported some benefits when using ECMO in ARDS.
      • Davies AR
      • Jones D
      • Bailey M
      • et al.
      Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome.
      • Noah MA
      • Peek GJ
      • Finney SJ
      • et al.
      Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza A(H1N1).
      • Peek GJ
      • Mugford M
      • Tiruvoipati R
      • et al.
      Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial.
      • Combes A
      • Hajage D
      • Capellier G
      • et al.
      Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
      The first landmark trial published in 2009 was a United Kingdom based multicenter RCT (CESAR trial) where 180 patients were randomized to receive conventional management or were referred to a single center for consideration for VV-ECMO. Adult patients with severe (Murray score for acute lung injury >3 or pH <7.2) but reversible respiratory failure were included and patients with high FiO2 (>0.8) or high peak airway pressure (>30 cmH2O) or mechanical ventilation more than 7 days or intracranial bleeding or contraindications to heparinization or any contraindication to continued active treatment were excluded. The study concluded that transferring patients with severe but reversible respiratory failure to a center with an ECMO based protocol improved survival (63 % in ECMO group vs 47% in control group) and was cost effective. However, this trial had many limitations as 24% of the patients in the ECMO group never received ECMO after being transferred to an ECMO center. Only 70% of patients in the control group received lung protective ventilation versus 93% in the ECMO group. Despite the limitations, the CESAR trials showed that VV-ECMO had a role in managing patients with severe ARDS and importance of transferring patients to specialized ECMO centers.
      • Peek GJ
      • Mugford M
      • Tiruvoipati R
      • et al.
      Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial.
      More recently, the EOLIA trial was published in 2018 which was a multicenter international RCT where 249 adult patients with severe ARDS (P/F <50 mmHg for >3 h or P/F <80 mmHg for > 6 h or pH < 7.25 with pCO2 > 60 mmHg for > 6 h) were randomized to early VV-ECMO or standard lung protective ventilation.
      • Combes A
      • Hajage D
      • Capellier G
      • et al.
      Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
      This trial did address the limitations of the CESAR trial by implementing a strict lung protective ventilation protocol in both groups, ECMO initiation before transfer and crossover to ECMO was allowed for control group patients with refractory hypoxemia (defined as SpO2 < 80% for > 6 h) and no irreversible multiorgan failure. At 60 days, the difference in mortality rate was not statistically significant between both groups (35% in ECMO group versus 46% in control group, p = 0.09) and 28% of control group patients crossed over to ECMO group had a57% mortality rate. It was hypothesized that one of the main reasons the trial was not able to demonstrate mortality difference between the groups was because the study was underpowered.
      • Patel B
      • Chatterjee S
      • Davignon S
      • Herlihy JP
      Extracorporeal membrane oxygenation as rescue therapy for severe hypoxemic respiratory failure.
      A meta-analysis of 3 trials with 504 patients using VV-ECMO versus standard care showed decrease in morality with VV-ECMO (RR, 0.64; 95% CI, 0.51-0.79).
      • Munshi L
      • Telesnicki T
      • Walkey A
      • Fan E
      Extracorporeal life support for acute respiratory failure. A systematic review and metaanalysis.
      Of note, in both the CESAR and EOLIA trials less than 25% of the screened patients were eligible for the study since it is considered unethical to withhold crossover to ECMO group from the control group, it might be difficult to perform a large study within a reasonable time frame that can show a significant survival benefit with using VV-ECMO in ARDS. Currently the most widely accepted indications ECMO consideration in respiratory failure are Murray score > 3, refractory hypoxemia (P/F < 100) despite lung protective ventilation, neuromuscular blockade and prone positioning when indicated or persistent respiratory acidosis with pH < 7.2.
      • Patel B
      • Chatterjee S
      • Davignon S
      • Herlihy JP
      Extracorporeal membrane oxygenation as rescue therapy for severe hypoxemic respiratory failure.
      ,
      • Griffiths MJD
      • McAuley DF
      • Perkins GD
      • et al.
      Guidelines on the management of acute respiratory distress syndrome.
      Absolute contraindication for ECMO include: terminal illness with life expectancy < 6 months, uncontrolled metastatic cancer, acute intracranial hemorrhage or infarction and any contradiction to systemic anticoagulation. The most common complications of VV-ECMO were bleeding (29.3%), neurological complications (7.1%) including intracranial hemorrhage, ischemic stroke, brain death and seizures.
      • Patel B
      • Chatterjee S
      • Davignon S
      • Herlihy JP
      Extracorporeal membrane oxygenation as rescue therapy for severe hypoxemic respiratory failure.
      ,
      • Vaquer S
      • de Haro C
      • Peruga P
      • Oliva JC
      • Artigas A
      Systematic review and meta-analysis of complications and mortality of veno-venous extracorporeal membrane oxygenation for refractory acute respiratory distress syndrome.
      Given the above evidence, the guidelines endorsed by British Thoracic Society suggest using ECMO in the selected patient group mentioned above and ATS/European Respiratory Society (ERS)/SCCM have no definitive recommendations for or against ECMO in severe ARDS.
      • Griffiths MJD
      • McAuley DF
      • Perkins GD
      • et al.
      Guidelines on the management of acute respiratory distress syndrome.
      ,
      • Fan E
      • Del Sorbo L
      • Goligher EC
      • et al.
      An official American Thoracic Society/European Society of Intensive Care Medicine/society of critical care medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome.
      In conclusion, the use of ECMO should be considered in a select number of patients with severe ARDS on lung protective ventilation with Murray Score >3 or pH < 7.2 due to uncompensated hypercapnia. Additional factors such as age, comorbidities, etiology of ARDS and availability of ECMO also need to be taken into consideration

      Fluid Restriction in ARDS

      The inflammatory processes associated with ARDS lead to increased capillary leak and pulmonary edema. The FACTT and FACTT lite trials showed that in patients with ARDS, fluid conservative strategies that are based on central venous pressure, urine output with or without pulmonary artery occlusion pressure had more ICU and ventilator free days when compared to liberal fluid strategies, however there was no difference in mortality between the two groups.
      • Wiedemann HP
      • Wheeler AP
      • Bernard GR
      • et al.
      Comparison of two fluid-management strategies in acute lung injury.
      ,
      • Grissom CK
      • Hirshberg EL
      • Dickerson JB
      • et al.
      Fluid management with a simplified conservative protocol for the acute respiratory distress syndrome*.

      Summary

      ARDS is a frequently encountered and potentially life-threatening condition for patients in the intensive care unit. Outcomes of these patients can be significantly improved with implementation of current guidelines and this concise review on effective and ineffective therapies for ARDS would be helpful for the clinicians providing care for these patients (Table 5).
      TABLE 5The current guidelines for management of ARDS.
      InterventionARDS SeverityLevel of recommendation/ strength of evidence
      Lung protective ventilation
      American Thoracic Society/European Society of intensive care medicine/society of critical care medicine clinical practice guideline
      (tidal volume of 4-8mL/Kg predicted body weight and plateau pleasure of <30 cm H2O)
      All ARDSStrong/ moderate
      Prone positioning for more than 12 hours a day
      American Thoracic Society/European Society of intensive care medicine/society of critical care medicine clinical practice guideline
      SevereStrong/ moderate
      Higher PEEP
      American Thoracic Society/European Society of intensive care medicine/society of critical care medicine clinical practice guideline
      Moderate or severeConditional/ moderate
      Recruitment maneuvers (Sustained hyperinflation)
      American Thoracic Society/European Society of intensive care medicine/society of critical care medicine clinical practice guideline
      Moderate or severeConditional/ low
      Cisatracurium
      Society of critical care medicine guidelines
      Moderate or severe (P/F <150)Weak/ low
      Methylprednisolone
      Society of critical care medicine guidelines
      Moderate or severeConditional/ moderate
      ECMO
      Recommendations endorsed by British Thoracic Society
      SevereWeak/ low
      low asterisk American Thoracic Society/European Society of intensive care medicine/society of critical care medicine clinical practice guideline
      a Society of critical care medicine guidelines
      low asterisklow asterisk Recommendations endorsed by British Thoracic Society

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